The present invention relates to novel benzofuryl-xcex1-pyrone derivatives and to medicines containing them as active ingredients. More specifically, the invention relates to novel benzofuryl-xcex1-pyrone derivatives and to lipid metabolism enhancers, arteriosclerosis prophylactic agents, arteriosclerosis treatment agents, triglyceride biosynthesis inhibitors, blood triglyceride lowering agents or blood HDL elevating agents containing them as active ingredients.
Blood cholesterol and triglycerides (TG) themselves are generally insoluble in blood, and they exist as lipoproteins by binding with apolipoproteins. In the body, triglycerides are biosynthesized primarily in the liver from acetyl CoA as the starting substance which is produced from sugars, etc., by 6 different enzymes and one enzyme group (acetyl CoA carboxylase, the fatty acid synthase group, fatty acyl CoA synthase, glycerophosphoric acid acyl transferase, lysophosphatidic acid acyl transferase, phosphatidic acid phosphatase and diacylglycerol acyl transferase), and are secreted from the liver into the blood as lipoproteins.
The condition of a higher-than-normal cholesterol and/or triglyceride blood level is known as hyperlipidemia. The condition termed hyperlipidemia is classified into 6 types based on the lipoproteins in the blood, according to the Fredrickson classification (WHO classification). Types I, IV and V are characterized by increased triglycerides only, type IIa by increased cholesterol, and types IIb and III by increases in both (xe2x80x9cSogo Rinshoxe2x80x9d, 43, 871(1994)). This means that present hyperlipidemia drugs (that lower only cholesterol or that lower both cholesterol and triglycerides) cannot always be appropriately applied for all hyperlipidemia cases. In particular, type IV accounts for 40 to 50% of male hyperlipidemia patients (xe2x80x9cRinsho to Kenkyuxe2x80x9d, 69, 318(1992)). Most secondary onset forms accompanying diabetes are also type IV (xe2x80x9cSogo Rinshoxe2x80x9d, 43, 878(1994)).
Hypertriglyceridemia is a condition in which blood triglyceride levels are increased, and in the past few years it has been receiving attention among clinical physicians and pharmaceutical manufacturers as a risk factor in arteriosclerosis and ischemic diseases.
Because most attention in the field of hyperlipidemia, which includes hypertriglyceridemia, has been focused on cholesterol alone, which is directly implicated in arteriosclerosis, few drugs have been developed with the aim of lowering triglycerides, and treatment of hypertriglyceridemia has been limited to the use of clofibrate-based hypolipidemic drugs or nicotinic acid preparations as the existing hypolipidemic drugs. Because these must be used in high doses and many action sites have been reported, there are concerns about a number of related side-effects (The Lipid, 5, 65 to 72(1994)). It would therefore be highly desirable to find a new type of drug that has a triglyceride-lowering effect at low doses, exhibits few side-effects and has a clear action mechanism.
Hypertriglyceridemia occurs as a result of various causes, including genetic background and, as mentioned above, secondary onset accompanying diabetes, etc. (xe2x80x9cSogo Rinshoxe2x80x9d, 43, 878(1994)); more specifically, it is attributed to:
A. accelerated triglyceride synthesis (secretion) in the liver, and
B. delayed decomposition of synthesized triglycerides (present in the blood as lipoproteins) by lipoprotein lipase (LPL) (xe2x80x9cRinsho to Kenkyuxe2x80x9d, 69, 340(1992)). In particular, for hypertriglyceridemia accompanying diabetes, A. is said to be the cause of non-insulin-dependent diabetes mellitus (NIDDM), while B. is said to be the cause of insulin-dependent diabetes mellitus (IDDM) (xe2x80x9cRinsho to Kenkyuxe2x80x9d, 69, 379(1992)). Consequently, the action mechanism of therapeutic agents for hypertriglyceridemia is believed to be inhibition of triglyceride synthesis (secretion) in the liver and/or accelerated decomposition of synthesized triglycerides (present in the blood as lipoproteins) by lipoprotein lipase (LPL).
In the prior art there have been known xcex1-pyrone derivatives with substitution of a heteroaromatic ring at the C-6 position, for example, in WO 9635664, WO 9514013, WO 9514014, EP 588137, U.S. Pat. No. 4,668,803, FR 2665445, Japanese Unexamined Patent Publication SHO No. 49-5976, Japanese Unexamined Patent Publication No. 8-503216, Japanese Unexamined Patent Publication No. 9-505291, Japanese Unexamined Patent Publication No. 9-505293, Japanese Unexamined Patent Publication No. 9-505294, Japanese, Unexamined Patent Publication No. 9-505295, or for example, in Tetrahedron Letters, 37, 6461 (1996), J. Chem. Research (S), 86 (1994), Chem. Pharm. Bull., 32, 1665 (1984), Chem. Ber., 100, 658 (1967) and J. Org. Chem., 54, 3985 (1989).
However, no explanation or suggestion has been published regarding a triglyceride biosynthesis inhibiting effect, blood triglyceride lowering effect or blood HDL elevating effect for any of these xcex1-pyrone derivatives of the prior art.
Of the prior art publications, WO 9635664 and EP 588137 describe compounds with a structural feature wherein phenyl is a substituent at the C-3 position of the xcex1-pyrone ring, but no description or suggestion is given regarding the use of an alkyl group instead of a phenyl group as the substituent at the C-3 position of the xcex1-pyrone ring.
Similarly, U.S. Pat. No. 4,668,803 among the prior art publications describes xcex1-pyrone derivatives wherein the substituent at the C-3 position is an acyl group of 2 to 11 carbons or a phenyl group, but no description or suggestion is given regarding the use of an alkyl group instead of an acyl group of 2 to 11 carbons or a phenyl group as the substituent at the C-3 position of the xcex1-pyrone ring.
Also, FR 2665445 among the prior art publications describes xcex1-pyrone derivatives with xe2x80x94S(O)nxe2x80x94R1 as a substituent at the C-4 position, wherein n is 1 or 2 and R1 represents an alkyl group of 1 to 6 carbons, a benzyl group or a phenyl group. However, no description or suggestion is given regarding the use of OH, OCOR or OSO2R instead of xe2x80x94S(O)nxe2x80x94R1 as the substituent at the C-4 position of the xcex1-pyrone ring.
Likewise, Japanese Unexamined Patent Publication No. 49-5976 among the prior art publications describes xcex1-pyrone derivatives with hydrogen, a lower alkyl group or phenyl as a substituent at the C-4 position, but no description or suggestion is given regarding the use of OH, OCOR or OSO2R instead of hydrogen, a lower alkyl group or phenyl as the substituent at the C-4 position of the xcex1-pyrone ring.
Likewise, Chem. Ber., 100, 658 (1967) among the prior art publications describes xcex1-pyrone derivatives with hydrogen, methyl or ethyl as a substituent at the C-4 position, but no description or suggestion is given regarding the use of OH, OCOR or OSO2R instead of hydrogen, methyl or ethyl as the substituent at the C-4 position of the xcex1-pyrone ring.
Likewise, J. Chem. Research (S), 86(1994) among the prior art publications describes xcex1-pyrone derivatives with an SMe group as a substituent at the C-4 position, but no description or suggestion is given regarding the use of OH, OCOR or OSO2R instead of an SMe group as the substituent at the C-4 position of the xcex1-pyrone ring.
In addition, Tetrahedron Letters, 37, 6461 (1996), Chem. Pharm. Bull., 32, 1665 (1984) and J. Org. Chem., 54, 3985 (1989) among the prior art publications describe xcex1-pyrone derivatives with a pyridyl group substituent at the C-6 position, but no description or suggestion is given regarding the use of a benzofuryl group instead of a pyridyl group as the substituent at the C-6 position of the xcex1-pyrone ring.
It is an object of the present invention to provide benzofuryl-xcex1-pyrone derivatives, and especially novel benzofuryl-xcex1-pyrone derivatives having a benzofuryl group as a substituent at the C-6 position of the xcex1-pyrone ring.
It is another object of the invention to provide lipid metabolism enhancers, arteriosclerosis prophylactic agents or arteriosclerosis treatment agents, and especially to provide triglyceride biosynthesis inhibitors, blood triglyceride lowering agents or blood HDL elevating agents, that contain as active ingredients the novel benzofuryl-xcex1-pyrone derivatives having a benzofuryl group as a substituent at the C-6 position of the xcex1-pyrone ring.
The present inventors have conducted much research in light of the prior art cited above, and as a result the inventors have found that benzofuryl-xcex1-pyrone derivatives, and especially benzofuryl-xcex1-pyrone derivatives having a benzofuryl group as a substituent at the C-6 position of the xcex1-pyrone ring, have a triglyceride biosynthesis inhibiting effect, a blood triglyceride lowering effect and a blood HDL elevating effect; the present invention have been achieved after still further research on the same.
Specifically, the present invention provides benzofuryl-xcex1-pyrone derivatives (and salts thereof) represented by the following structural formula (I) 
wherein
R1 represents hydrogen or an alkyl group of 1 to 5 carbons;
R2 represents hydrogen, xe2x80x94COxe2x80x94R5 (wherein R5 represents hydrogen, an alkyl group of 1 to 5 carbons with optional substituents, a cycloalkyl group of 3 to 7 carbons, an aryl group of 6 to 10 carbons or a heterocycle), or xe2x80x94SO2R6 (wherein R6 represents an optionally halogen-substituted alkyl group of 1 to 5 carbons or aryl group of 6 to 10 carbons);
R3 represents hydrogen, an alkyl group of 1 to 5 carbons, an alkenyl group of 2 to 5 carbons, an alkynyl group of 2 to 5 carbons, a cycloalkyl group of 3 to 7 carbons, a cycloalkyl group of 3 to 7 carbons-alkyl group of 1 to 5 carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons, an alkoxy group of 1 to 5 carbons or an aryloxy group of 6 to 10 carbons;
R4 is a substituent at the C-4 position, C-5 position, C-6 position or C-7 position of the benzofuran ring and represents:
R4a which represents hydrogen, a nitro group, a cyano group, a halogen atom, a heterocycle, an alkenyl group of 2 to 5 carbons, an alkynyl group of 2 to 5 carbons, an aryl group of 6 to 10 carbons, Axe2x95x90CH(CH2)nxe2x80x94 (wherein A represents an alicyclic heterocycle, xe2x80x9cxe2x95x90xe2x80x9d represents a double bond and n represents 0, 1 or 2), Axe2x95x90CH(CH2)mOxe2x80x94 (wherein A represents an alicyclic heterocycle, xe2x80x9cxe2x95x90xe2x80x9d represents a double bond and m represents 1, 2 or 3), Axe2x80x94SO2xe2x80x94(CH2)mxe2x80x94 (wherein A represents an alicyclic heterocycle and m represents 1, 2 or 3), xe2x80x94OR7 (wherein R7 represents hydrogen, a cycloalkyl group of 3 to 7 carbons, an aryl group of 6 to 10 carbons, a heterocycle, an optionally halogen-substituted alkylsulfonyl group of 1 to 4 carbons, or an arylsulfonyl group of 6 to 10 carbons), xe2x80x94Oxe2x80x94COxe2x80x94R8 (wherein R8 represents hydrogen, an alkyl group of 1 to 4 carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons or a heterocycle), xe2x80x94NR9R10 (wherein R9 and R10 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, an aralkyl group of 7 to 20 carbons, a phenyl group, a heterocycle, xe2x80x94SO2xe2x80x94R11 (wherein R11 represents an optionally halogen-substituted alkyl group of 1 to 12 carbons, a heterocycle-substituted alkyl group of 1 to 6 carbons, an aryl group of 6 to 10 carbons, a heterocycle or an aralkyl group of 7 to 20 carbons) or xe2x80x94COxe2x80x94R12 (wherein R12 represents hydrogen, an alkyl group of 1 to 12 carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons, a heterocycle, an alkoxy group of 1 to 10 carbons, a heterocycle-substituted alkyl group of 1 to 6 carbons, an aryloxy group of 6 to 10 carbons, a heteroaryloxy group or an aralkyloxy group of 7 to 20 carbons)), xe2x80x94COxe2x80x94R13 (wherein R13 represents hydrogen, xe2x80x94OH, an alkyl group of 1 to 4 carbons, an aryl group of 6 to 10 carbons, a heterocycle, an alkoxy group of 1 to 4 carbons, an aryloxy group of 6 to 10 carbons or an aralkyloxy group of 7 to 20 carbons), or xe2x80x94COxe2x80x94NR14R15 (wherein R14 and R15 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, a cycloalkyl group of 3 to 7 carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons, a heterocycle or a heterocycle-substituted alkyl group of 1 to 4 carbons);
R4b which represents a saturated or unsaturated alkoxy group of 1 to 6 carbons optionally substituted with 1 to 3 groups selected from the group consisting of halogens, cycloalkyl groups of 3 to 7 carbons, phenyl, naphthyl, heterocycles, xe2x80x94OR16 (wherein R16 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group or a heterocycle), xe2x80x94Oxe2x80x94COxe2x80x94R16 (wherein R16 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group or a heterocycle), xe2x80x94NR17R18 (wherein R17 and R18 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, a heterocycle, an alkylsulfonyl group of 1 to 4 carbons, a phenylsulfonyl group, xe2x80x94SO2-Het (wherein Het represents a heterocycle), an aminosulfonyl group, a methylaminosulfonyl group, a dimethylaminosulfonyl group, a diethylaminosulfonyl group, or an alkyl group of 1 to 4 carbons substituted with 1 or 2 groups selected from among phenyl, heterocycles, phenoxy, xe2x80x94O-Het (wherein Het represents a heterocycle) and hydroxyl, xe2x80x94NHxe2x80x94COxe2x80x94R19 (wherein R19 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group, a heterocycle, an alkoxy group of 1 to 4 carbons or a benzyloxy group), xe2x80x94COxe2x80x94R20 (wherein R20 represents hydrogen, a heterocycle, an alkoxy group of 1 to 4 carbons, a phenoxy group, a benzyloxy group or xe2x80x94OR21 (wherein R21 represents hydrogen or a heterocycle)), and xe2x80x94COxe2x80x94NR22R23 (wherein R22 and R23 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, a benzyl group or a heterocycle); or
R4c which represents an alkyl group of 1 to 4 carbons optionally substituted with 1 to 3 groups selected from the group consisting of halogens, cycloalkyl groups of 3 to 7 carbons, phenyl, naphthyl, heterocycles, xe2x80x94SH, xe2x80x94OR16 (wherein R16 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group or a heterocycle), xe2x80x94Oxe2x80x94COxe2x80x94R16 (wherein R16 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group or a heterocycle), xe2x80x94NR17R18 (wherein R17 and R18 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, a heterocycle, an alkylsulfonyl group of 1 to 4 carbons, a phenylsulfonyl group, xe2x80x94SO2-Het (wherein Het represents a heterocycle), an aminosulfonyl group, a methylaminosulfonyl group, a dimethylaminosulfonyl group, a diethylaminosulfonyl group, or an alkyl group of 1 to 4 carbons substituted with 1 or 2 groups selected from among phenyl, heterocycles, phenoxy, xe2x80x94O-Het (wherein Het represents a heterocycle) and hydroxyl, xe2x80x94NHxe2x80x94COxe2x80x94R19 (wherein R19 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group, a heterocycle, an alkoxy group of 1 to 4 carbons or a benzyloxy group), xe2x80x94COxe2x80x94R20 (wherein R20 represents hydrogen, a heterocycle, an alkoxy group of 1 to 4 carbons, a phenoxy group, a benzyloxy group or xe2x80x94OR21 (wherein R21 represents hydrogen or a heterocycle)) and xe2x80x94COxe2x80x94NR22R23 (wherein R22 and R23 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, a benzyl group or a heterocycle); and
the numbers in italics represents the positions on the benzofuran ring.
The present invention further provides pharmaceutical compositions comprising a therapeutically effective dose of the benzofuryl-xcex1-pyrone derivatives represented by structural formula (I) above or their salts, with pharmaceutically acceptable carriers.
The invention still further provides lipid metabolism enhancers, triglyceride biosynthesis inhibitors, blood triglyceride lowering agents, blood HDL elevating agents, arteriosclerosis prophylactic agents and arteriosclerosis treatment agents containing as active ingredients the benzofuryl-xcex1-pyrone derivatives represented by structural formula (I) above or their salts.
The terms used alone or in conjunction with other terms throughout the present specification will now be explained. However, the invention is in no way restricted by the specific examples listed below.
xe2x80x9cAlkylxe2x80x9d means a linear or branched alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl or 3-pentyl.
xe2x80x9cAlkenylxe2x80x9d means a linear or branched alkenyl group such as vinyl, 1-propenyl, aryl, isopropenyl, 2-butenyl, 3-butenyl, 1-pentenyl or 2-pentenyl.
xe2x80x9cAlkynylxe2x80x9d means a linear or branched alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl or 4-pentynyl.
xe2x80x9cCycloalkylxe2x80x9d means a cycloalkyl group of 3 to 7 carbons such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
A xe2x80x9ccycloalkyl group of 3 to 7 carbons-alkyl group of 1 to 5 carbonsxe2x80x9d is a group comprising the aforementioned cycloalkyl group of 3 to 7 carbons and alkyl group of 1 to 5 carbons, and for example, there may be mentioned cyclopropylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and cycloheptylmethyl.
xe2x80x9cArylxe2x80x9d means an aromatic ring of 6 to 10 carbons such as phenyl or naphthyl.
A xe2x80x9cheterocyclexe2x80x9d is a heterocycle containing as constituents of the ring 1 to 4 hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur, and it may be a 5- or 6-membered heteroaromatic group such as imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, oxazolyl or isoxazolyl, or a 5- to 7-membered heteroalicyclic group such as thiazolidinyl, oxazolidinyl, imidazolidinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, homopiperazinyl, tetrahydrofuryl, tetrahydropyranyl, dioxolanyl, dioxanyl, oxazinyl, thiazinyl, diazinyl or pyrazolidinyl; this also includes bicyclic groups condensed onto benzene, cycloalkyl groups of 3 to 7 carbons and other heteroaromatic rings or heteroalicyclic rings, the heteroaromatic ring or heteroalicyclic ring may also be optionally substituted, and when chemically possible, the nitrogen atom or sulfur atom may be in an oxidized form.
xe2x80x9cHeteroarylxe2x80x9d means a heteroaromatic group of the heterocycles defined above.
xe2x80x9cAralkylxe2x80x9d represents a group of 7 to 20 carbons comprising the aforementioned alkyl group of 1 to 5 carbons and aryl group of 6 to 10 carbons, and for example, there may be mentioned benzyl, phenethyl, phenylpropyl, benzhydryl, trityl and naphthylmethyl.
xe2x80x9cAlkoxyxe2x80x9d means a linear or branched alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, 3-pentyloxy, 2,2-dimethylpropoxy, n-hexyloxy, 4-methylpentyloxy or 2-ethylbutoxy.
xe2x80x9cUnsaturated alkoxyxe2x80x9d means a linear or branched unsaturated alkoxy group such as vinyloxy, allyloxy, 2-propenyloxy, 2-propynyloxy, 2-methyl-2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy, 2-butynyloxy, 2-pentenyloxy, 3-hexenyloxy, 5-hexenyloxy or 5-hexynyloxy.
xe2x80x9cAryloxyxe2x80x9d means an aryloxy group of 6 to 10 carbons such as phenoxy or naphthyloxy.
xe2x80x9cAralkyloxyxe2x80x9d represents a group comprising the aforementioned alkoxy group of 1 to 5 carbons and aryl group of 6 to 10 carbons, and for example, there may be mentioned benzyloxy, phenethyloxy, phenylpropoxy, trityloxy and naphthylmethyloxy.
xe2x80x9cCycloalkyloxyxe2x80x9d means a cycloalkyloxy group of 3 to 7 carbons such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy.
xe2x80x9cAcylxe2x80x9d means a linear or branched acyl group of 1 to 6 carbons such as formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, trimethylacetyl or 3,3,3-trimethylpropionyl.
xe2x80x9cArylcarbonylxe2x80x9d means an arylcarbonyl group of 7 to 11 carbons such as benzoyl or naphthylcarbonyl.
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkylsulfonyl group of 1 to 5 carbons such as methanesulfonyl, ethanesulfonyl or n-propanefulfonyl.
xe2x80x9cArylsulfonylxe2x80x9d means an arylsulfonyl group of 6 to 10 carbons such as phenylsulfonyl or naphthalenesulfonyl.
The rings of the xe2x80x9carylxe2x80x9d, xe2x80x9cphenylxe2x80x9d, xe2x80x9cnaphthylxe2x80x9d and xe2x80x9cheterocyclexe2x80x9d may be substituted with 1 to 4 substituents selected from the group consisting of, for example, xe2x80x94OH, carboxyl, cyano, phenyl, heterocycles, xe2x80x94SO2NH2, xe2x80x94SO3H, alkylsulfamoyl groups such as methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, etc., phenylsulfamoyl, benzylsulfamoyl, morpholinesulfonyl, alkylsulfonyl groups such as methanesulfonyl, ethanesulfonyl, n-propanesulfonyl, etc., arylsulfonyl groups such as phenylsulfonyl, naphthalenesulfonyl, etc., amino, methylenedioxy, alkoxy groups of 1 to 5 carbons such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentyloxy, etc., alkylamino groups such as methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, t-butylamino, etc., acylamino groups such as formamino, acetylamino, propionylamino, n-butyrylamino, etc., alkoxycarbonylamino groups such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, n-butoxycarbonylamino, t-butoxycarbonylamino, etc., aralkyloxycarbonylamino groups such as benzyloxycarbonylamino, naphthylmethyloxycarbonylamino, etc., alkylsulfonylamino groups such as methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino, etc., arylsulfonylamino groups such as phenylsulfonylamino, naphthalenesulfonylamino, etc., nitro, hydroxymethyl, alkyl groups of 1 to 5 carbons such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, etc., aralkyl groups such as benzyl, phenethyl, trityl, naphthylmethyl, etc., aralkyloxy groups such as benzyloxy, phenethyloxy, phenylpropoxy, trityloxy, naphthylmethyloxy, etc., acyl groups such as formyl, acetyl, propionyl, n-butyryl, isobutyryl, n-valeryl, trimethylacetyl, 3,3,3-trimethylpropionyl, etc., alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, t-butoxycarbonyl, etc., aryloxycarbonyl groups such as phenoxycarbonyl, naphthyloxycarbonyl, etc., aralkyloxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, etc., carbamoyl, alkylcarbamoyl groups such as methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, n-propylcarbamoyl, n-butylcarbamoyl, etc., halogenated methyl groups such as chloromethyl, bromomethyl, trifluoromethyl, etc., and halogen atoms, i.e. fluorine, chlorine, bromine and iodine; when chemically possible, these may be substituted with 1 to 3 oxo groups or thiooxo groups.
In formula (I) above, R1 represents hydrogen or an alkyl group of 1 to 5 carbons. As alkyl groups of 1 to 5 carbons there may be mentioned, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl and 3-pentyl.
As preferred groups for R1 there may be mentioned hydrogen, methyl, ethyl and isopropyl, and methyl may be mentioned as a particularly preferred group for R1.
In formula (I) above, R2 represents hydrogen, xe2x80x94COxe2x80x94R5 (wherein R5 represents hydrogen, an alkyl group of 1 to 5 carbons with optional substituents, a cycloalkyl group of 3 to 7 carbons, an aryl group of 6 to 10 carbons or a heterocycle), or xe2x80x94SO2R6 (wherein R6 represents an optionally halogen-substituted alkyl group of 1 to 5 carbons, or an aryl group of 6 to 10 carbons).
When R2 is xe2x80x94COxe2x80x94R5 and the R5 group is an alkyl group of 1 to 5 carbons with an optional substituent, the alkyl group of 1 to 5 carbons for R5 may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, 3-pentyl, etc., among which methyl, ethyl and isopropyl are preferred.
Optional substituents of the alkyl group of 1 to 5 carbons for R5 include all alkyl group substituents known to those skilled in the art and, for example, they include halogen atoms, xe2x80x94OH, carboxyl groups, formyl groups, acyl groups, cyano groups, nitro groups, amino groups, mercapto groups, sulfonate groups, aryl groups of 6 to 10 carbons, heterocycles, cycloalkyl groups of 3 to 7 carbons and their protected forms; more specifically, there may be mentioned xe2x80x94OH; hydroxyl protected with an alkyl group of 1 to 4 carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons, a heterocycle, an acyl group of 1 to 5 carbons, an arylcarbonyl group of 7 to 11 carbons or an aralkylcarbonyl group of 8 to 21 carbons; xe2x80x94Oxe2x80x94CO-Het (wherein Het represents a heterocycle); cycloalkyl groups of 3 to 7 carbons; aryl groups of 6 to 10 carbons; heterocycles; amino groups; amino groups protected with an alkyl group of 1 to 4 carbons, an aralkyl group of 7 to 20 carbons, an optionally halogen-substituted alkylsulfonyl group of 1 to 4 carbons, an arylsulfonyl group of 6 to 10 carbons, an acyl group of 1 to 5 carbons, an arylcarbonyl group of 7 to 11 carbons, an aralkylcarbonyl group of 8 to 21 carbons, an alkoxycarbonyl group of 2 to 5 carbons, an aralkyloxycarbonyl group of 8 to 21 carbons or a heterocycle; xe2x80x94NHxe2x80x94CO-Het (wherein Het represents a heterocycle); acyl groups of 1 to 5 carbons; carboxyl groups; alkoxycarbonyl groups of 2 to 5 carbons; aryloxycarbonyl groups of 7 to 11 carbons; aralkyloxycarbonyl groups of 8 to 21 carbons; xe2x80x94COxe2x80x94O-Het (wherein Het represents a heterocycle); carbamoyl groups, alkylcarbamoyl groups of 2 to 5 carbons; aralkylcarbamoyl groups of 8 to 21 carbons; xe2x80x94COxe2x80x94NH-Het (wherein Het represents a heterocycle); and xe2x80x94CO-Het (wherein Het represents a heterocycle). As preferred substituents among these there may be mentioned phenyl, aryloxy, amino, t-butoxycarbonylamino, benzyloxycarbonylamino, (benzyloxycarbonylamino)methylamino, acetylamino and morpholinylcarbonyl.
When R2 is xe2x80x94COR5 and the R5 group is a cycloalkyl group of 3 to 7 carbons, the cycloalkyl group of 3 to 7 carbons for R5 may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., among which cyclohexyl is preferred.
When R2 is xe2x80x94COR5 and the R5 group is an aryl group of 6 to 10 carbons, the aryl group of 6 to 10 carbons for R5 may be, for example, phenyl, naphthyl, etc., among which phenyl is preferred.
When R2 is xe2x80x94COR5 and the R5 group is a heterocycle, the heterocycle for R5 may be, for example, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl, etc., among which pyridyl, pyrrolidinyl and furyl are preferred.
As preferred groups for R5 there may be mentioned alkyl groups of 1 to 5 carbons with optional substituents, among which there may be mentioned methyl, methyl or ethyl substituted with phenyl, aryloxy, amino, t-butoxycarbonylamino, benzyloxycarbonylamino, (benzyloxycarbonyl)-N-methylamino, acetylamino or morpholinylcarbonyl, and isopropyl; aryl groups of 6 to 10 carbons, among which there may be mentioned phenyl; and heterocycles, among which there may be mentioned pyridyl, pyrrolidinyl and furyl.
When R2 is xe2x80x94SO2R6 and the R6 group is an optionally halogen-substituted alkyl group of 1 to 5 carbons, the optionally halogen-substituted alkyl group of 1 to 5 carbons for R6 may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, chloromethyl, bromomethyl, trifluoromethyl, etc., among which methyl and trifluoromethyl are preferred.
When R2 is xe2x80x94SO2R6 and R6 is an aryl group of 6 to 10 carbons, the aryl group of 6 to 10 carbons for R6 may be, for example, phenyl, naphthyl, etc., among which phenyl is preferred.
As preferred groups for R6 there may be mentioned optionally halogen-substituted alkyl groups of 1 to 5 carbons, and as particularly preferred groups for R6 there may be mentioned methyl and trifluoromethyl.
As preferred groups for R2 there may be mentioned hydrogen, xe2x80x94COR70 (wherein R70 represents an alkyl group of 1 to 5 carbons with an optional substituent, an aryl group of 6 to 10 carbons or a heterocycle) and optionally halogen-substituted alkylsulfonyl groups of 1 to 5 carbons, and as particularly preferred groups for R2 there may be mentioned hydrogen, xe2x80x94COR71 (wherein R71 represents s methyl group; a methyl or ethyl group substituted with phenyl, aryloxy, amino, t-butoxycarbonylamino, benzyloxycarbonylamino, (benzyloxycarbonyl)-N-methylamino, acetylamino or morpholinylcarbonyl; an isopropyl group; a phenyl group; a pyridyl group; a pyrrolidinyl group; or a furyl group), methanesulfonyl and trifluoromethanesulfonyl.
In formula (I) above, R3 represents hydrogen, an alkyl group of 1 to 5 carbons, an alkenyl group of 2 to 5 carbons, an alkynyl group of 2 to 5 carbons, a cycloalkyl group of 3 to 7 carbons, a cycloalkyl of 3 to 7 carbons-alkyl group of 1 to 5 carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons, an alkoxy group of 1 to 5 carbons or an aryloxy group of 6 to 10 carbons.
When R3 is an alkyl group of 1 to 5 carbons, the alkyl group of 1 to 5 carbons may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, etc., among which methyl, ethyl, isopropyl and n-pentyl are preferred.
When R3 is an alkenyl group of 2 to 5 carbons, the alkenyl group of 2 to 5 carbons may be vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, etc., among which 2-butenyl is preferred.
When R3 is an alkynyl group of 2 to 5 carbons, the alkylnyl group of 2 to 5 carbons may be ethynyl, 2-propynyl, 1-propynyl, isopropynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, etc., among which 2-butynyl is preferred.
When R3 is a cycloalkyl group of 3 to 7 carbons, the cycloalkyl group of 3 to 7 carbons may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., among which cyclohexyl is preferred.
When R3 is a cycloalkyl of 3 to 7 carbons-alkyl group of 1 to 5 carbons, the cycloalkyl of 3 to 7 carbons-alkyl group of 1 to 5 carbons may be, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, etc., among which cyclopentylmethyl is preferred.
When R3 is an aryl group of 6 to 10 carbons, the aryl group of 6 to 10 carbons may be, for example, phenyl, naphthyl, etc., among which phenyl is preferred.
When R3 is an aralkyl group of 7 to 20 carbons, the aralkyl group of 7 to 20 carbons may be, for example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, etc., among which benzyl is preferred.
When R3 is an alkoxy group of 1 to 5 carbons, the alkoxy group of 1 to 5 carbons may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, etc., among which methoxy is preferred.
When R3 is an aryloxy group of 6 to 10 carbons, the aryloxy group of 6 to 10 carbons may be, for example, phenoxy, naphthyloxy, etc., among which phenoxy is preferred.
As preferred groups for R3 there may be mentioned alkyl groups of 1 to 5 carbons, alkenyl groups of 2 to 5 carbons, cycloalkyl groups of 3 to 7 carbons-alkyl groups of 1 to 5 carbons and aralkyl groups of 7 to 20 carbons, and as particularly preferred groups for R3 there may be mentioned alkyl groups of 1 to 5 carbons, among which methyl, ethyl, isopropyl and n-pentyl are preferred; cycloalkyl groups of 3 to 7 carbons-alkyl groups of 1 to 5 carbons, among which cyclopentylmethyl is preferred; and benzyl.
In formula (I) above, R4 is a substituent at the C-4 position, C-5 position, C-6 position or C-7 position of the benzofuran ring and represents:
R4a which represents hydrogen, a nitro group, a cyano group, a halogen atom, a heterocycle, an alkenyl group of 2 to 5 carbons, an alkynyl group of 2 to 5 carbons, an aryl group of 6 to 10 carbons, Axe2x95x90CH(CH2)nxe2x80x94 (wherein A represents an alicyclic heterocycle, xe2x80x9cxe2x95x90xe2x80x9d represents a double bond and n represents 0, 1 or 2), Axe2x95x90CH(CH2)mOxe2x80x94 (wherein A represents an alicyclic heterocycle, xe2x80x9cxe2x95x90xe2x80x9d represents a double bond and m represents 1, 2 or 3), Axe2x80x94SO2xe2x80x94(CH2)mxe2x80x94 (wherein A represents an alicyclic heterocycle and m represents 1, 2 or 3), xe2x80x94OR7 (wherein R7 represents hydrogen, a cycloalkyl group of 3 to 7 carbons, an aryl group of 6 to 10 carbons, a heterocycle or an optionally halogen-substituted alkylsulfonyl group of 1 to 4 carbons or arylsulfonyl group of 6 to 10 carbons), xe2x80x94Oxe2x80x94COxe2x80x94R8 (wherein R8 represents hydrogen, an alkyl group of 1 to 4 carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons or a heterocycle), xe2x80x94NR9R10 (wherein R9 and R10 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, an aralkyl group of 7 to 20 carbons, a phenyl group, a heterocycle, xe2x80x94SO2xe2x80x94R11 (wherein R11 represents an optionally halogen-substituted alkyl group of 1 to 12 carbons, a heterocycle-substituted alkyl group of 1 to 6 carbons, an aryl group of 6 to 10 carbons, a heterocycle or an aralkyl group of 7 to 20 carbons) or xe2x80x94COxe2x80x94R12 (wherein R12 represents hydrogen, an alkyl group of 1 to 12 carbons, an, aryl group of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons, a heterocycle, an alkoxy group of 1 to 10 carbons, a heterocycle-substituted alkyl group of 1 to 6 carbons, an aryloxy group of 6 to 10 carbons, a heteroaryloxy group or an aralkyloxy group of 7 to 20 carbons)), xe2x80x94COxe2x80x94R13 (wherein R13 represents hydrogen, xe2x80x94OH, an alkyl group of 1 to 4 carbons, an aryl group of 6 to 10 carbons, a heterocycle, an alkoxy group of 1 to 4 carbons, an aryloxy group of 6 to 10 carbons or an aralkyloxy group of 7 to 20 carbons) or xe2x80x94COxe2x80x94NR14R15 (wherein R14 and R15 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, a cycloalkyl group of 3 to 7 carbons, an aryl group of 6 to 10 carbons, an aralkyl group of 7 to 20 carbons, a heterocycle or a heterocycle-substituted alkyl group of 1 to 4 carbons);
R4b which represents a saturated or unsaturated alkoxy group of 1 to 6 carbons optionally substituted with 1 to 3 groups selected from the group consisting of halogens, cycloalkyl groups of 3 to 7 carbons, phenyl, naphthyl, heterocycles, xe2x80x94OR16 (wherein R16 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group or a heterocycle), xe2x80x94Oxe2x80x94COxe2x80x94R16 (wherein R16 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group or a heterocycle), xe2x80x94NR17R18 (wherein R17 and R18 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, a heterocycle, an alkylsulfonyl group of 1 to 4 carbons, a phenylsulfonyl group, xe2x80x94SO2-Het (wherein Het represents a heterocycle), an aminosulfonyl group, a methylaminosulfonyl group, a dimethylaminosulfonyl group, a diethylaminosulfonyl group, or an alkyl group of 1 to 4 carbons substituted with 1 or 2 groups selected from among phenyl, heterocycles, phenoxy, xe2x80x94O-Het (wherein Het represents a heterocycle) and hydroxyl, xe2x80x94NHxe2x80x94COxe2x80x94R19 (wherein R19 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group, a heterocycle, an alkoxy group of 1 to 4 carbons or a benzyloxy group), xe2x80x94COxe2x80x94R20 (wherein R20 represents hydrogen, a heterocycle, an alkoxy group of 1 to 4 carbons, a phenoxy group, a benzyloxy group or xe2x80x94OR21 (wherein R21 represents hydrogen or a heterocycle)) and xe2x80x94COxe2x80x94NR22R23 (wherein R22 and R23 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, a benzyl group or a heterocycle); or
R4c which represents an alkyl group of 1 to 4 carbons optionally substituted with 1 to 3 groups selected from the group consisting of halogens, cycloalkyl groups of 3 to 7 carbons, phenyl, naphthyl, heterocycles, xe2x80x94SH, xe2x80x94OR16 (wherein R16 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group or a heterocycle), xe2x80x94Oxe2x80x94COxe2x80x94R16 (wherein R16 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group or a heterocycle), xe2x80x94NR17R18 (wherein R17 and R18 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, a heterocycle, an alkylsulfonyl group of 1 to 4 carbons, a phenylsulfonyl group, xe2x80x94SO2-Het (wherein Het represents a heterocycle), an aminosulfonyl group, a methylaminosulfonyl group, a dimethylaminosulfonyl group, a diethylaminosulfonyl group, or an alkyl group of 1 to 4 carbons substituted with 1 or 2 groups selected from among phenyl, heterocycles, phenoxy, xe2x80x94O-Het (wherein Het represents a heterocycle) and hydroxyl, xe2x80x94NHxe2x80x94COxe2x80x94R19 (wherein R19 represents hydrogen, an alkyl group of 1 to 4 carbons, a phenyl group, a naphthyl group, a benzyl group, a heterocycle, an alkoxy group of 1 to 4 carbons or a benzyloxy group), xe2x80x94COxe2x80x94R20 (wherein R20 represents hydrogen, a heterocycle, an alkoxy group of 1 to 4 carbons, a phenoxy group, a benzyloxy group or xe2x80x94OR21 (wherein R21 represents hydrogen or a heterocycle)) and xe2x80x94COxe2x80x94NR22R23 (wherein R22 and R23 each independently represents hydrogen, an alkyl group of 1 to 4 carbons, a benzyl group or a heterocycle).
When R4 is R4a, there may be mentioned as specific examples of R4a, hydrogen; nitro; cyano; halogen atoms such as fluorine, chlorine, bromine and iodine; heterocycles such as imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, 6-oxo-4,5-benzo-1,3-oxazin-2-yl, 1-oxoisoindolin-2-yl, pyrrolidinyl, 2,5-dioxopyrrolidinyl, piperidyl, 2,6-dioxopiperidyl, 1-(4-bromobenzoyl)piperidin-4-yl, morpholinyl, piperazinyl, 2,3-dioxopiperazinyl, homopiperazinyl, tetrahydrofuryl and tetrahydropyranyl; alkenyl groups such as vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl, 3-butenyl, 1-pentenyl and 2-pentenyl; alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl and 4-pentynyl; aryl groups such as phenyl and naphthyl; hydroxyl; cycloalkyloxy groups such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy; aryloxy groups such as phenoxy and naphthyloxy; groups represented by xe2x80x94O-Het (wherein Het represents a heterocycle), such as imidazolyloxy, thiazolyloxy, isothiazolyloxy, pyrazolyloxy, triazolyloxy, pyrrolyloxy, pyridyloxy, pyrimidinyloxy, pyrazinyloxy, furyloxy, thienyloxy, isoxazolyloxy, thiazolidinyloxy, oxazolidinyloxy, imidazolidinyloxy, pyrrolidinyloxy, piperidyloxy, morpholinyloxy, piperazinyloxy, tetrahydrofuryloxy and tetrahydropyranyloxy; optionally halogen-substituted alkylsulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, n-propanesulfonyloxy and trifluoromethanesulfonyloxy; arylsulfonyloxy groups such as phenylsulfonyloxy and naphthalenesulfonyloxy; acyloxy groups such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and trimethylacetyloxy; arylcarboxy groups such as benzoyloxy and naphthylcarboxy; aralkylcarboxy groups such as phenylacetyloxy, 2-phenylpropionyloxy, 3-phenylbutyryloxy, diphenylacetyloxy and naphthylacetyloxy; groups represented by xe2x80x94Oxe2x80x94CO-Het (wherein Het represents a heterocycle), such as imidazolylcarboxy, thiazolylcarboxy, isothiazolylcarboxy, pyrazolylcarboxy, triazolylcarboxy, pyrrolylcarboxy, pyridylcarboxy, pyrimidinylcarboxy, pyrazinylcarboxy, furylcarboxy, thienylcarboxy, isoxazolylcarboxy, thiazolidinylcarboxy, oxazolidinylcarboxy, imidazolidinylcarboxy, pyrrolidinylcarboxy, piperidylcarboxy, morpholinylcarboxy, piperazinylcarboxy, tetrahydrofurylcarboxy and tetrahydropyranylcarboxy; amino; alkylamino groups such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino and dibutylamino; aralkylamino groups such as benzylamino and dibenzylamino; heterocycle-substituted amino groups such as imidazolylamino, N-methyl-N-imidazolylamino, thiazolylamino, N-methyl-N-thiazolylamino, isothiazolylamino, pyrazolylamino, triazolylamino, N-methyl-N-triazolylamino, pyrrolylamino, pyridylamino, N-methyl-N-pyridylamino, dipyridylamino, pyrimidinylamino, pyrazinylamino, furylamino, thienylamino, isoxazolylamino, thiazolidinylamino, oxazolidinylamino, imidazolidinylamino, pyrrolidinylamino, N-methyl-N-pyrrolidinylamino, piperidylamino, morpholinylamino, N-methyl-N-morpholinylamino, tetrahydrofurylamino and tetrahydropyranylamino; optionally halogen-substituted alkylsulfonylamino groups such as methanesulfonylamino, N-methyl-N-methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino and trifluoromethanesulfonylamino; arylsulfonylamino groups such as phenylsulfonylamino, N-methyl-N-phenylsulfonylamino, N-(4-chlorophenylsulfonyl)-N-methylamino and naphthalenesulfonylamino; acylamino groups such as formylamino, acetylamino, N-methyl-N-acetylamino, propionylamino, butyrylamino, isobutyrylamino, N-methyl-N-isobutyrylamino and trimethylacetylamino; arylcarbonylamino groups such as benzoylamino, N-methyl-N-benzoylamino and naphthylcarbonylamino; aralkylcarbonylamino groups such as phenylacetylamino, N-methyl-N-phenylacetylamino, 2-phenylpropionylamino, 3-phenylbutyrylamino, diphenylacetylamino and naphthylacetylamino; amino groups substituted with a group represented by xe2x80x94CO-Het (wherein Het represents a heterocycle), such as imidazolylcarbonylamino, N-methyl-N-imidazolylcarbonylamino, thiazolylcarbonylamino, N-methyl-N-thiazolylcarbonylamino, pyridylcarbonylamino, N-methyl-N-pyridylcarbonylamino, pyrimidinylcarbonylamino, N-methyl-N-pyrimidinylcarbonylamino, pyrazinylcarbonylamino, N-methyl-N-pyrazinylcarbonylamino, furylcarbonylamino, thienylcarbonylamino, N-methyl-N-thienylcarbonylamino, N-methyl-N-oxazolylcarbonylamino, N-methyl-N-tetrazolylcarbonylamino, thiazolidinylcarbonylamino, oxazolidinylcarbonylamino, imidazolidinylcarbonylamino, pyrrolidinylcarbonylamino and piperidylcarbonylamino; alkoxycarbonylamino groups such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, t-butoxycarbonylamino and N-methyl-N-(t-butoxycarbonyl)amino; aryloxycarbonylamino groups such as phenoxycarbonylamino and naphthyloxycarbonylamino; aralkyloxycarbonylamino groups such as benzyloxycarbonylamino, phenethyloxycarbonylamino, phenylpropoxycarbonylamino, benzhydryloxycarbonylamino and naphthylmethoxycarbonylamino; formyl; carboxyl; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl; aryloxycarbonyl groups such as phenoxycarbonyl and naphthyloxycarbonyl; aralkyloxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropoxycarbonyl, benzhydryloxycarbonyl and naphthylmethoxycarbonyl; acyl groups such as acetyl, propionyl, butyryl and isobutyryl; arylcarbonyl groups such as benzoyl and naphthylcarbonyl; groups represented by xe2x80x94CO-Het (wherein Het represents a heterocycle), such as imidazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, pyrazolylcarbonyl, triazolylcarbonyl, pyrrolylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, thiazolidinylcarbonyl, oxazolidinylcarbonyl, imidazolidinylcarbonyl, pyrrolidinylcarbonyl, piperidylcarbonyl, morpholinylcarbonyl, piperazinylcarbonyl and 1,3,4-trihydroisoquinon-2-ylcarbonyl; carbamoyl groups such as carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl, 4-bromo-2-cyanophenylcarbamoyl, N-methyl-N-phenylcarbamoyl, benzylcarbamoyl, N-benzyl-N-methylcarbamoyl, N-methyl-N-phenethylcarbamoyl, dibenzylcarbamoyl, imidazolylcarbamoyl, N-imidazolyl-N-methylcarbamoyl, N-benzimidazolyl-N-methylcarbamoyl, thiazolylcarbamoyl, N-methyl-N-thiazolylcarbamoyl, benzothiazolylcarbamoyl, N-benzothiazolyl-N-methylcarbamoyl, isothiazolylcarbamoyl, oxazolylcarbamoyl, N-methyl-N-oxazolylcarbamoyl, benzoxazolylcarbamoyl, N-benzoxazolyl-N-methylcarbamoyl, pyrazolylcarbamoyl, triazolylcarbamoyl, pyrrolylcarbamoyl, pyridylcarbamoyl, N-methyl-N-pyridylcarbamoyl, N-methyl-N-(pyridylmethyl)carbamoyl, pyrimidinylcarbamoyl, pyrazinylcarbamoyl, furylcarbamoyl, thienylcarbamoyl, isoxazolylcarbamoyl, thiazolidinylcarbamoyl, oxazolidinylcarbamoyl, imidazolidinylcarbamoyl, pyrrolidinylcarbamoyl, piperidylcarbamoyl, tetrahydrofurylcarbamoyl and tetrahydropyranylcarbamoyl; groups represented by Axe2x95x90CH(CH2)nxe2x80x94 (wherein A represents an alicyclic heterocycle, xe2x80x9cxe2x95x90xe2x80x9d represents a double bond and n represents 0, 1, or 2), such as (3,5-dioxo-2,4-thiazolidinylidene)methyl, (3,5-dioxo-2,4-oxazolidinylidene)methyl, (2,5-dioxoimidazolidin-4-ylidene)methyl, (5-oxo-3-thioxo-2,4-thiazolidinylidene)methyl, (2,4,6-trioxo-3,5-diazaperhydroinylidene)methyl and (3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene)methyl; groups represented by Axe2x95x90CH(CH2)mOxe2x80x94 (wherein A represents an alicyclic heterocycle, xe2x80x9cxe2x95x90xe2x80x9d represents a double bond and m represents 1, 2, or 3), such as 2-(3,5-dioxo-2,4thiazolidinylidene)ethoxy, 2-(3,5-dioxo-2,4-oxazolidinylidene)ethoxy, 2-(2,5-dioxoimidazolidin-4-ylidene)ethoxy, 2-(5-oxo-3-thioxo-2,4-thiazolidinylidene)ethoxy, 2-(2,4,6-trioxo-3,5-diazaperhydroinylidene)ethoxy and 2-(3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene)ethoxy; and groups represented by Axe2x80x94SO2xe2x80x94(CH2)mxe2x80x94 (wherein A represents an alicyclic heterocycle and m represents 1, 2, or 3), such as (3,5-dioxo-2,4-thiazolidinyl)sulfonylmethyl, (3,5-dioxo-2,4-oxazolidinyl)sulfonylmethyl, (2,5-dioxoimidazolidin-4-yl)sulfonylmethyl, and (5-oxo-3-thioxo-2,4-thiazolidinyl)sulfonylmethyl.
As preferred groups for R4a there may be specifically mentioned, for example, hydrogen, nitro, cyano, bromine, imidazolyl, thiazolyl, pyridyl, pyrimidinyl, furyl, thienyl, morpholinyl, piperazinyl, hydroxyl, pyrrolidinyloxy, piperidyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, phenylsulfonyloxy, acetyloxy, benzoyloxy, imidazolylcarboxy, thiazolylcarboxy, pyridylcarboxy, pyrimidinylcarboxy, pyrazinylcarboxy, dimethylamino, ethylamino, diethylamino, dibenzylamino, imidazolylamino, thiazolylamino, pyridylamino, pyrimidinylamino, N-methyl-N-methanesulfonylamino, phenylsulfonylamino, N-methyl-N-phenylsulfonylamino, N-methyl-N-acetylamino, N-methyl-N-isobutyrylamino, N-methyl-N-benzoylamino, N-methyl-N-phenylacetylamino, N-methyl-N-imidazolylcarbonylamino, N-methyl-N-thiazolylcarbonylamino, N-methyl-N-thienylcarbonylamino, N-methyl-N-oxazolylcarbonylamino, N-methyl-N-tetrazolylcarbonylamino, N-methyl-N-pyridylcarbonylamino, N-methyl-N-pyrazinylcarbonylamino, N-methyl-N-pyrimidinylcarbonylamino, N-methyl-N-(t-butoxycarbonyl)amino, dimethylcarbamoyl, cyclohexylcarbamoyl, phenylcarbamoyl, N-methyl-N-phenylcarbamoyl, N-benzyl-N-methylcarbamoyl, imidazolylcarbamoyl, benzimidazolylcarbamoyl, thiazolylcarbamoyl, N-methyl-N-thiazolylcarbamoyl, benzothiazolylcarbamoyl, isothiazolylcarbamoyl, pyrazolylcarbamoyl, triazolylcarbamoyl, pyrrolylcarbamoyl, pyridylcarbamoyl, N-methyl-N-pyridylcarbamoyl, pyrimidinylcarbamoyl, pyrazinylcarbamoyl, isoxazolylcarbamoyl, piperidylcarbamoyl, 1,3,4-trihydroisoquinolin-2-ylcarbonyl, formyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, acetyl, benzoyl, (3,5-dioxo-2,4-thiazolidinylidene)methyl, (3,5-dioxo-2,4-oxazolidinylidene)methyl, (2,5-dioxoimidazolidin-4-ylidene)methyl, (5-oxo-3-thioxo-2,4-thiazolidinylidene)methyl, 2-(3,5-dioxo-2,4-thiazolidinylidene)ethoxy, 2-(3,5-dioxo-2,4-oxazolidinylidene)ethoxy, 2-(2,5-dioxoimidazolidin-4-ylidene)ethoxy, 2-(5-oxo-3-thioxo-2,4-thiazolidinylidene)ethoxy, (3,5-dioxo-2,4-thiazolidinyl)sulfonylmethyl, (3,5-dioxo-2,4-oxazolidinyl)sulfonylmethyl, (2,5-dioxoimidazolidin-4-yl)sulfonylmethyl and (5-oxo-3-thioxo-2,4-thiazolidinyl)sulfonylmethyl.
As particularly preferred groups for R4a there may be specifically mentioned, for example, hydrogen, nitro, cyano, bromine, thienyl, piperazinyl, trifluoromethanesulfonyloxy, phenylsulfonyloxy, acetyloxy, dimethylamino, dibenzylamino, N-methyl-N-methanesulfonylamino, N-methyl-N-phenylsulfonylamino, N-methyl-N-acetylamino, N-methyl-N-isobutyrylamino, N-methyl-N-benzoylamino, N-methyl-N-phenylacetylamino, N-methyl-N-thienylcarbonylamino, N-methyl-N-oxazolylcarbonylamino, N-methyl-N-thiazolylcarbonylamino, N-methyl-N-pyridylcarbonylamino, thiazolylcarbamoyl, benzothiazolylcarbamoyl, benzimidazolylcarbamoyl, N-methyl-N-phenylcarbamoyl, 1,3,4-trihydroisoquinolin-2-ylcarbonyl, methoxycarbonyl, isopropoxycarbonyl, and (3,5-dioxo-2,4-thiazolidinylidene)methyl.
When R4 is R4b, there may be mentioned as specific examples of substituents on the alkoxy groups of 1 to 4 carbons for R4a, for example, halogen atoms such as fluorine, chlorine, bromine and iodine; cycloalkyl groups of 3 to 7 carbons such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; aryl groups of 6 to 10 carbons such as phenyl, aminophenyl and naphthyl; heterocycles such as imidazolyl, N-tosylimidazolyl, thiazolyl, 2-(morpholinesulfonyl)thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, 2-methoxypyridyl, 5-hydroxypyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, 2-(morpholinesulfonyl)thienyl, oxazolyl, 2-phenyloxazolyl, isoxazolyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyranyl and dioxolanyl; xe2x80x94OH; alkoxy groups of 1 to 4 carbons such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, 3-pentyloxy, 2,2-dimethylpropoxy, n-hexyloxy, 4-methylpentyloxy and 2-ethylbutoxy; aryloxy groups of 6 to 10 carbons such as phenoxy and naphthyloxy; benzyloxy; groups represented by xe2x80x94O-Het (wherein Het represents a heterocycle), such as pyridyloxy and piperidyloxy; acyloxy groups of 1 to 5 carbons such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and trimethylacetyloxy; arylcarboxy groups of 7 to 11 carbons such as benzoyloxy and naphthylcarboxy; phenylacetyloxy; groups represented by xe2x80x94Oxe2x80x94CO-Het (wherein Het represents a heterocycle), such as imidazolylcarboxy, thiazolylcarboxy, isothiazolylcarboxy, pyrazolylcarboxy, triazolylcarboxy, pyrrolylcarboxy, pyridylcarboxy, pyrimidinylcarboxy, pyrazinylcarboxy, furylcarboxy, thienylcarboxy, isoxazolylcarboxy, thiazolidinylcarboxy, oxazolidinylcarboxy, imidazolidinylcarboxy, pyrrolidinylcarboxy, piperidylcarboxy, morpholinylcarboxy, piperazinylcarboxy, tetrahydrofurylcarboxy and tetrahydropyranylcarboxy; amino; monosubstituted or disubstituted amino groups such as methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, dibutylamino, benzylamino, dibenzylamino, 2-hydroxy-2-phenethylamino, 2-hydroxy-3-phenoxypropylamino, imidazolylamino, thiazolylamino, isothiazolylamino, pyrazolylamino, triazolylamino, pyrrolylamino, pyridylamino, dipyridylamino, pyrimidinylamino, pyrazinylamino, furylamino, thienylamino, isoxazolylamino, thiazolidinylamino, oxazolidinylamino, imidazolidinylamino, pyrrolidinylamino, piperidylamino, tetrahydrofurylamino and tetrahydropyranylamino; optionally halogen-substituted alkylsulfonylamino groups of 1 to 4 carbons such as methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino and trifluoromethanesulfonylamino; phenylsulfonylamino; acylamino groups of 1 to 5 carbons such as dimethylaminosulfonylamino, methylaminosulfonylamino, formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino and trimethylacetylamino; arylcarbonylamino groups of 7 to 11 carbons such as benzoylamino and naphthylcarbonylamino; phenylacetylamino; groups represented by xe2x80x94NHxe2x80x94CO-Het (wherein Het represents a heterocycle), such as imidazolylcarbonylamino, thiazolylcarbonylamino, isoxazolylcarbonylamino, pyridylcarbonylamino, pyrimidinylcarbonylamino, pyrazinylcarbonylamino, furylcarbonylamino, thienylcarbonylamino, pyrrolidinylcarbonylamino, piperidylcarbonylamino and morpholinylcarbonylamino; alkoxycarbonylamino groups of 2 to 5 carbons such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino and t-butoxycarbonylamino; benzyloxycarbonylamino; formyl; carboxy; alkoxycarbonyl groups of 2 to 5 carbons such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl; phenoxycarbonyl; benzyloxycarbonyl; acyl groups of 2 to 5 carbons such as acetyl, propionyl, butyryl and isobutyryl; groups represented by xe2x80x94CO-Het (wherein Het represents a heterocycle) such as imidazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, pyrazolylcarbonyl, triazolylcarbonyl, pyrrolylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, thiazolidinylcarbonyl, oxazolidinylcarbonyl, imidazolidinylcarbonyl, pyrrolidinylcarbonyl, piperidylcarbonyl, morpholinylcarbonyl and piperazinylcarbonyl; groups represented by xe2x80x94COxe2x80x94O-Het (wherein Het represents a heterocycle), such as pyridyloxycarbonyl and piperidyloxycarbonyl; and carbamoyl groups such as carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, benzylcarbamoyl, dibenzylcarbamoyl, imidazolylcarbamoyl, thiazolylcarbamoyl, isothiazolylcarbamoyl, pyrazolylcarbamoyl, triazolylcarbamoyl, pyrrolylcarbamoyl, pyridylcarbamoyl, pyrimidinylcarbamoyl, pyrazinylcarbamoyl, furylcarbamoyl, thienylcarbamoyl, isoxazolylcarbamoyl, thiazolidinylcarbamoyl, oxazolidinylcarbamoyl, imidazolidinylcarbamoyl, pyrrolidinylcarbamoyl, piperidylcarbamoyl, tetrahydrofurylcarbamoyl and tetrahydropyranylcarbamoyl.
As preferred groups for R4b there may be specifically mentioned, for example, saturated or unsaturated alkoxy groups such as methoxy, 2-propynyloxy, 2-butynyloxy, 3-hexenyloxy, 5-hexenyloxy and 2,2-dimethylpropoxy; halogen-substituted alkoxy groups such as 2-bromoethoxy and 2-chloroethoxy; cycloalkyl-alkoxy groups such as cyclopentylmethoxy and cyclohexylmethoxy; aryl-alkoxy groups such as benzyloxy, aminobenzyloxy, chlorobenzyloxy, fluorobenzyloxy, bromobenzyloxy, nitrobenzyloxy, (trifluoromethyl)benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy, methoxybenzyloxy, sulfamoylbenzyloxy, (methylenedioxy)benzyloxy, carboxybenzyloxy, (methoxycarbonyl)benzyloxy, n-butoxybenzyloxy, 3-phenylpropoxy, di(methoxyphenyl)methoxy, 2,2-diphenylethoxy, 1-methyl-1-phenylethoxy and naphthylmethoxy; heterocycle-substituted alkoxy groups such as thienylmethoxy, 2-(morpholinesulfonyl)thienylmethoxy, pyridylmethoxy, (5-hydroxypyridyl)methoxy, (2-methoxypyridyl)methoxy, 2-(pyridyl)ethoxy, pyrazinylmethoxy, pyrimidinylmethoxy, N-tosylimidazolylmethoxy, oxazolylmethoxy, 2-phenyloxazolylmethoxy, thiazolylmethoxy, 2-(morpholinesulfonyl)thiazolylmethoxy, (3,5-dioxo-2,4-thiazolidinyl)methoxy, N-methylpiperidylmethoxy, N-t-butoxycarbonylpiperidylmethoxy, N-acetylpiperidylmethoxy, N-methanesulfonylpiperidylmethoxy, (4-oxachroman-2-yl)methoxy, (3,3-dimethyl-2,4-dioxolanyl)methoxy, (1-methyl-3-oxetanyl)methoxy and 2-(morpholin-4-yl)ethoxy; alkoxy-alkoxy groups such as methoxymethyl and 2-ethoxyethoxy; benzyloxy-alkoxy groups such as 2-(benzyloxy)ethoxy; acyloxy-alkoxy groups such as 2-(acetyloxy)ethoxy; alkylamino-alkoxy groups such as bis(dimethylaminomethyl)methoxy; alkoxycarbonylamino-alkoxy groups such as 4-(t-butoxycarbonylamino)butoxy; and alkoxycarbonyl-alkoxy groups such as ethoxycarbonylmethoxy, 2-(methoxycarbonyl)ethoxy and 5-(ethoxycarbonyl)pentyloxy.
As particularly preferred groups for R4b there may be specifically mentioned, for example, methoxy, 2-propynyloxy, benzyloxy, aminobenzyloxy, chlorobenzyloxy, fluorobenzyloxy, (trifluoromethyl)benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy, methoxybenzyloxy, sulfamoylbenzyloxy, (methylenedioxy)benzyloxy, carboxybenzyloxy, (methoxycarbonyl)benzyloxy, n-butoxybenzyloxy, thienylmethoxy, 2-(morpholinesulfonyl)thienylmethoxy, pyridylmethoxy, (2-methoxypyridyl)methoxy, (5-hydroxypyridyl)methoxy, 2-(pyridyl)ethoxy, pyrazinylmethoxy, pyrimidinylmethoxy, N-tosylimidazolylmethoxy, oxazolylmethoxy, 2-phenyloxazolylmethoxy, thiazolylmethoxy, 2-(morpholinesulfonyl)thiazolylmethoxy, (3,5-dioxo-2,4-thiazolidinyl)methoxy, N-methylpiperidylmethoxy and methoxymethyl.
When R4 is R4c, there may be mentioned as specific examples of substituents on the alkoxy groups of 1 to 4 carbons for R4c, for example, halogen atoms such as fluorine, chlorine, bromine, iodine; cycloalkyl groups of 3 to 7 carbons such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; aryl groups of 6 to 10 carbons such as phenyl and naphthyl; heterocycles such as imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolidinyl, oxazolidinyl, 3,5-dioxooxazolidinyl, imidazolidinyl, 2-oxoimidazolidinyl, pyrrolidinyl, piperidyl, morpholinyl, pyrazolidinyl, 3,5-dioxopyrazolidinyl, piperazinyl, 2,5-dioxopiperazinyl, tetrahydrofuryl, tetrahydropyranyl and dioxolanyl; xe2x80x94SH; xe2x80x94OH; alkoxy groups of 1 to 4 carbons such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, 3-pentyloxy, 2,2-dimethylpropoxy, n-hexyloxy, 4-methylpentyloxy and 2-ethylbutoxy; aryloxy groups of 6 to 10 carbons such as phenoxy and naphthyloxy; benzyloxy; groups represented by xe2x80x94O-Het (wherein Het represents a heterocycle), such as pyridyloxy and piperidyloxy; acyloxy groups of 1 to 5 carbons such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy and trimethylacetyloxy; arylcarboxy groups of 7 to 11 carbons such as benzoyloxy and naphthylcarboxy; phenylacetyloxy; groups represented by xe2x80x94Oxe2x80x94CO-Het (wherein Het represents a heterocycle), such as imidazolylcarboxy, thiazolylcarboxy, isothiazolylcarboxy, pyrazolylcarboxy, triazolylcarboxy, pyrrolylcarboxy, pyridylcarboxy, pyrimidinylcarboxy, pyrazinylcarboxy, furylcarboxy, thienylcarboxy, isoxazolylcarboxy, thiazolidinylcarboxy, oxazolidinylcarboxy, imidazolidinylcarboxy, pyrrolidinylcarboxy, piperidylcarboxy, morpholinylcarboxy, piperazinylcarboxy, tetrahydrofurylcarboxy and tetrahydropyranylcarboxy; amino; monosubstituted or disubstituted amino groups such as methylamino, dimethylamino, ethylamino, 2-hydroxy-2-phenethylamino, 2-hydroxy-3-phenoxypropylamino, diethylamino, propylamino, dipropylamino, isopropylamino, diisopropylamino, dibutylamino, benzylamino, dibenzylamino, imidazolylamino, thiazolylamino, isothiazolylamino, pyrazolylamino, triazolylamino, pyrrolylamino, pyridylamino, dipyridylamino, pyrimidinylamino, pyrazinylamino, furylamino, thienylamino, isoxazolylamino, thiazolidinylamino, oxazolidinylamino, imidazolidinylamino, pyrrolidinylamino, piperidylamino, tetrahydrofurylamino and tetrahydropyranylamino; optionally halogen-substituted alkylsulfonylamino groups of 1 to 4 carbons such as methanesulfonylamino, ethanesulfonylamino, n-propanesulfonylamino and trifluoromethanesulfonylamino; phenylsulfonylamino; acylamino groups of 1 to 5 carbons such as formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino and trimethylacetylamino; arylcarbonylamino groups of 7 to 11 carbons such as benzoylamino, 4-chlorobenzoylamino and naphthylcarbonylamino; phenylacetylamino; groups represented by xe2x80x94NHxe2x80x94CO-Het (wherein Het represents a heterocycle), such as imidazolylcarbonylamino, thiazolylcarbonylamino, pyridylcarbonylamino, pyrimidinylcarbonylamino, pyrazinylcarbonylamino, furylcarbonylamino, thienylcarbonylamino, thiazolidinylcarbonylamino, oxazolidinylcarbonylamino, imidazolidinylcarbonylamino, pyrrolidinylcarbonylamino and piperidylcarbonylamino; alkoxycarbonylamino groups of 2 to 5 carbons such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino and t-butoxycarbonylamino; benzyloxycarbonylamino; formyl; carboxyl; alkoxycarbonyl groups of 2 to 5 carbons such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and t-butoxycarbonyl; phenoxycarbonyl; benzyloxycarbonyl; acyl groups of 2 to 5 carbons such as acetyl, propionyl, butyryl and isobutyryl; groups represented by xe2x80x94CO-Het (wherein Het represents a heterocycle), such as imidazolylcarbonyl, thiazolylcarbonyl, isothiazolylcarbonyl, pyrazolylcarbonyl, triazolylcarbonyl, pyrrolylcarbonyl, pyridylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbonyl, furylcarbonyl, thienylcarbonyl, isoxazolylcarbonyl, thiazolidinylcarbonyl, oxazolidinylcarbonyl, imidazolidinylcarbonyl, pyrrolidinylcarbonyl, piperidylcarbonyl, morpholinylcarbonyl and piperazinylcarbonyl; groups represented by xe2x80x94COxe2x80x94O-Het (wherein Het represents a heterocycle), such as pyridyloxycarbonyl and piperidyloxycarbonyl; and carbamoyl groups such as carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, dipropylcarbamoyl, benzylcarbamoyl, dibenzylcarbamoyl, imidazolylcarbamoyl, thiazolylcarbamoyl, isothiazolylcarbamoyl, pyrazolylcarbamoyl, triazolylcarbamoyl, pyrrolylcarbamoyl, pyridylcarbamoyl, pyrimidinylcarbamoyl, pyrazinylcarbamoyl, furylcarbamoyl, thienylcarbamoyl, isoxazolylcarbamoyl, thiazolidinylcarbamoyl, oxazolidinylcarbamoyl, imidazolidinylcarbamoyl, pyrrolidinylcarbamoyl, piperidylcarbamoyl, tetrahydrofurylcarbamoyl and tetrahydropyranylcarbamoyl.
As preferred groups for R4c there may be specifically mentioned, for example, phenethyl, xcex1-hydroxybenzyl, 1-(acetyloxy)ethyl and (3,5-dioxo-2,4-thiazolidinyl)methyl.
Thus, as specific preferred combinations for R1, R2, R3, and R4 there may be mentioned those in which, for example, R1 is methyl, ethyl, or isopropyl, R2 is an acetyl or propionyl group substituted with a substituent selected from the group consisting of phenyl, phenoxy, amino, t-butoxycarbonylamino, benzyloxycarbonylamino, (benzyloxycarbonyl)-N-methylamino, acetylamino, and morpholinylcarbonyl; or hydrogen, acetyl, propionyl, isobutyryl, benzoyl, pyridylcarbonyl, pyrrolidinylcarbonyl, furylcarbonyl, methanesulfonyl, or trifluoromethanesulfonyl, R3 is methyl, ethyl, isopropyl, n-pentyl, cyclopentylmethyl or benzyl, and R4 is hydrogen, nitro, cyano, bromine, thienyl, piperazinyl, trifluoromethanesulfonyloxy, phenylsulfonyloxy, acetyloxy, dimethylamino, dibenzylamino, N-methyl-N-methanesulfonylamino, N-methyl-N-phenylsulfonylamino, N-methyl-N-acetylamino, N-methyl-N-isobutyrylamino, N-methyl-N-benzoylamino, N-methyl-N-phenylacetylamino, N-methyl-N-imidazolylcarbonylamino, N-methyl-N-thiazolylcarbonylamino, N-methyl-N-pyridylcarbonylamino, N-methyl-N-pyrimidinylcarbonylamino, N-methyl-N-pyrazinylcarbonylamino, N-methyl-N-thienylcarbonylamino, N-methyl-N-oxazolylcarbonylamino, N-methyl-N-(t-butoxycarbonyl)amino, thiazolylcarbamoyl, methoxycarbonyl, isopropoxycarbonyl, (3,5-dioxo-2,4-thiazolidinylidene)methyl, methoxy, 2-propynyloxy, benzyloxy, aminobenzyloxy, chlorobenzyloxy, fluorobenzyloxy, (trifluoromethyl)benzyloxy, dichlorobenzyloxy, dimethylbenzyloxy, methoxybenzyloxy, sulfamoylbenzyloxy, (methylenedioxy)benzyloxy, carboxybenzyloxy, (methoxycarbonyl)benzyloxy, n-butoxybenzyloxy, thienylmethoxy, 2-(morpholinesulfonyl)thienylmethoxy, pyridylmethoxy, (2-methoxypyridyl)methoxy, 2-(pyridyl)ethoxy, pyrazinylmethoxy, pyrimidinylmethoxy, N-tosylimidazolylmethoxy, oxazolylmethoxy, 2-phenyloxazolylmethoxy, thiazolylmethoxy, 2-(morpholinesulfonyl)thiazolylmethoxy, (3,5-dioxo-2,4-thiazolidinyl)methoxy, N-methylpiperidylmethoxy, methoxymethyl, phenethyl, xcex1-hydroxybenzyl, 1-(acetyloxy)ethyl or (3,5-dioxo-2,4-thiazolidinyl)methyl.
As specific compounds represented by structural formula (I) above there may be mentioned those compounds mentioned in the examples of the present specification, but additional compounds that may be mentioned included the following:
6-(benzofuran-2-yl)-3-ethyl-4-hydroxy-5-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-hydroxy-5-methyl-3-n-propyl-2H-pyran-2-one;
4-acetyloxy-6-(benzofuran-2-yl)-5-ethyl-3-methyl-2H-pyran-2-one;
4-acetyloxy-6-(benzofuran-2-yl)-5-isopropyl-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-(2-(t-butoxycarbonylamino)acetyloxy)-5-ethyl-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-5-ethyl-3-methyl-4-(2-pyrrolidon-5-ylcarboxy)-2H-pyran-2-one;
4-(2-aminoacetyloxy)-6-(benzofuran-2-yl)-5-ethyl-3-methyl-2H-pyran-2-one;
4-(3-acetylamino-4-morpholinyl-4-oxobutyryloxy)-6-(benzofuran-2-yl)-5-ethyl-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-propionyloxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-5-ethyl-4-isobutyryloxy-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-isovaleryloxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(2,2,2-trimethylacetyloxy)-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-cyclohexylcarboxy-3,5-dimethyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-(2-cyclopropylacetyloxy)-3,5-dimethyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-(2-cyclopentylacetyloxy)-3,5-dimethyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-benzoyloxy-5-ethyl-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-benzoyloxy-5-isopropyl-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-naphthylcarboxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-imidazolylcarboxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-thiazolylcarboxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-triazolylcarboxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-5-ethyl-3-methyl-4-pyridylcarboxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-pyrimidinylcarboxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-pyrazinylcarboxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-thienylcarboxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-isoxazolylcarboxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-imidazolylacetyloxy)-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-pyridylacetyloxy)-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-methoxyacetyloxy)-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-t-butoxyacetyloxy)-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-hydroxy-3-methyl-5-n-propyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-5-cyclopentyl-4-hydroxy-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-5-cyclopropylmethyl-4-hydroxy-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-5-cyclohexylmethyl-4-hydroxy-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-hydroxy-3-methyl-5-naphthylmethyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-5-ethoxy-4-hydroxy-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-hydroxy-5-isopropoxy-3-methyl-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-(2-thienyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-((3,5-dioxo-2,4-oxazolidinylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-((2,5-dioxoimidazolidin-4-ylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-((5-oxo-3-thioxo-2,4-thiazolidinylidene)methyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-((2,4,6-trioxo-3,5-diazaperhydroinylidene)methyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-((3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-(2-(3,5-dioxo-2,4-thiazolidinylidene)ethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-(2-(3,5-dioxo-2,4-oxazolidinylidene)ethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-(2-(2,5-dioxoimidazolidin-4-ylidene)ethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-(5-oxo-3-thioxo-2,4-thiazolidinylidene)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-(2,4,6-trioxo-3,5-diazaperhydroinylidene)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-(2-(3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinylidene)ethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinyl)sulfonylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-((3,5-dioxo-2,4-oxazolidinyl)sulfonylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-((2,5-dioxoimidazolidin-4-yl)sulfonylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-((5-oxo-3-thioxo-2,4-thiazolidinyl)sulfonylmethyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinyl)methoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-((3,5-dioxo-2,4-oxazolidinyl)methoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-((2,5-dioxoimidazolidin-4-yl)methoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-((5-oxo-3-thioxo-2,4-thiazolidinyl)methoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-((2,4,6-trioxo-3,5-diazaperhydroinyl)methoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-((3,5-dimethyl-2,4,6-trioxo-3,5-diazaperhydroinyl)methoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-phenylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one;
6-(5-(N-benzyl-N-methylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-pyridylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-thiazolylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(pyridylmethyl)carbamoyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-(2-hydroxy-2-phenethylamino)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-(2-hydroxy-3-phenoxypropylamino)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-hydroxy-3-aminopropoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-hydroxy-3-phenylaminopropoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-(2-hydroxy-2-phenethylamino)propyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-(2-hydroxy-3-phenoxypropylamino)propyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-(2-hydroxy-2-phenethylamino)ethyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-(2-hydroxy-3-phenoxypropylamino)ethyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-(3,5-dioxopyrazolidin-4-ylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-(3,5-dioxooxazolidin-4-ylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-oxoimidazolidinylmethyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-(2,5-dioxopiperazinylmethyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(imidazolylmethyl)benzofuran-2-yl)-2H-pyran-2-one;
6-(5-(N-benzothiazolyl-N-methylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(6-oxo-4,5-benzoxazin-2-yl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-pyridylaminomethyl)benzofuran-2-yl)-2H-pyran-2-one;
6-(5-(4-bromo-2-cyanophenylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(3-pyridyl)aminomethyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(3-pyridyl)carbamoyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(4-(2-pyridyl)piperazinylcarbonyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(4-(2-pyrimidinyl)piperazinylcarbonyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(2-pyridyl)carbamoyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-(2-pyrimidinyl)carbamoyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-((2-pyridylmethyl)carbamoyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(triazolylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-(2,5-dioxopyrrolidinyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-(2,6-dioxopiperidinyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-(2,3-dioxopiperazinyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
6-(5-(2-(4-chlorobenzoylamino)ethyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
6-(5-(3-(acetylamino)propoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-(2-pyrazinylcarbonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-(2-pyridylcarbonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-(5-isoxazolylcarbonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-(morpholinylcarbonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-(methanesulfonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-(3-(dimethylaminosulfonylamino)propoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-(isoxazolylsulfonylamino)propoxy)benzofuran-2-yl)-2H-pyran-2-one;
6-(5-(N-acetylpiperidin-3-ylmethoxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-(2-pyridylcarbonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-(2-pyrazinylcarbonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-(5-isoxazolylcarbonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-(morpholinylcarbonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methanesulfonylpiperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-(N-(dimethylaminosulfonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-(5-thiazolylsulfonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one; and
3,5-dimethyl-4-hydroxy-6-(5-(N-(5-isoxazolylsulfonyl)piperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one.
As preferred specific compounds represented by structural formula (I) above there may be mentioned, for example, the following:
4-acetyloxy-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-benzoyloxy-3,5-dimethyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-methanesulfonyloxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-pyridylcarboxy)-2H-pyran-2-one;
3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinylidene)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinyl)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-hydroxy-3-methyl-5-n-pentyl-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-methoxybenzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(7-methoxybenzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(6-(trifluoromethanesulfonyloxy)benzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(6-(2-thienyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(6-methoxybenzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(5-pyrimidinylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(4-hydroxymethylbenzoyloxy)-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-(2-(N-carbobenzyloxy-N-methylamino)acetyloxy)-3,5-dimethyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(4-methoxybenzoyloxy)-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-phenylacetyloxy)-2H-pyran-2-one;
6-(benzofuran-2-yl)-5-ethyl-4-hydroxy-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-hydroxy-5-isopropyl-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-5-benzyl-4-hydroxy-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-isobutyryloxy-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-nitrobenzofuran-2-yl)-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-phenoxyacetyloxy)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-nitrobenzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-(dimethylamino)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
6-(5-(dibenzylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(2-thienylcarbonyl)amino)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(3-pyridylcarbonyl)amino)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-isobutyryl-N-methylamino)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-(phenylacetyl)amino)benzofuran-2-yl)-2H-pyran-2-one;
6-(5-(N-benzoyl-N-methylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
6-(5-(N-t-butoxycarbonyl-N-methylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
6-(5-(benzothiazolylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
6-(5-(benzimidazolylcarbamoyl)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(N-methyl-N-phenylcarbamoyl)benzofuran-2-yl)-2H-pyran-2-one;
6-(5-(N-(4-chlorophenylsulfonyl)-N-methylamino)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(1,3,4-trihydroisoquinolin-2-ylcarbonyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-morpholinylbenzofuran-2-yl)-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-isonicotinoyloxy-2H-pyran-2-one;
4-(2-aminoacetyloxy)-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
6-(5-benzyloxybenzofuran-2-yl)-4-(2-(t-butoxycarbonylamino)acetyloxy)-3,5-dimethyl-2H-pyran-2-one;
4-(2-aminoacetyloxy)-6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
4-(4-(acetylamino)benzoyloxy)-6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-4-nicotinoyloxy-2H-pyran-2-one;
6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-4-isonicotinoyloxy-2H-pyran-2-one;
6-(5-benzyloxybenzofuran-2-yl)-5-ethyl-4-hydroxy-3-methyl-2H-pyran-2-one;
5-ethyl-4-hydroxy-3-methyl-6-(5-(3-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-(2-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(5-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-6-(5-(2,4-dichloro-5-thiazolylmethoxy)benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-(4-methyl-5-thiazolyl)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-(2-(4-methyl-5-thiazolyl)ethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(4-methyl-5-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-(morpholinesulfonyl)-5-thiazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-(4-methyl-1-tosyl-5-imidazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(3-phenylpropionyloxy)-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-furoyloxy)-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-nicotinoyloxy-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-acetylamino-4-(morpholin-4-yl)-4-oxobutyryloxy)-2H-pyran-2-one;
4-acetyloxy-6-(5-bromobenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-5-cyclopentylmethyl-4-hydroxy-3-methyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-(1-carbobenzyloxy-2-pyrrolidon-5-ylcarboxy)-3,5-dimethyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(2-pyrrolidon-5-ylcarboxy)-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-(2-(t-butoxycarbonylamino)acetyloxy)-3,5-dimethyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-4-(2,4-dimethoxybenzoyloxy)-3,5-dimethyl-2H-pyran-2-one;
6-(benzofuran-2-yl)-3,5-dimethyl-4-(3-dimethylaminobenzoyloxy)-2H-pyran-2-one;
4-(4-(acetylamino)benzoyloxy)-6-(benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
3,5-dimethyl-6-(5-(2-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3,4-(methylenedioxy)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(5-hydroxy-3-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-(2-methoxy-5-pyridylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(l-methylpiperidin-3-ylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
6-(5-(4-carboxybenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-(trifluoromethyl)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-(trifluoromethyl)benzyloxy)benzofuran-2-yl)-2H-pyran-2-one;
6-(5-(3,4-dimethylbenzyloxy)benzofuran-2-yl)-3,5dimethyl-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-(2-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-(morpholinesulfonyl)-5-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-(2-(morpholinesulfonyl)-5-thienylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(4-oxazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-phenyl-4-oxazolylmethoxy)benzofuran-2-yl)-2H-pyran-2-one;
6-(5-(2,4-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
6-(5-(3,4-dichlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
6-(5-(4-n-butoxybenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(6-(1,2,3,4-tetrahydronaphthalen-1-yloxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(2-propyn-1-yloxy)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-6-(5-(3-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-6-(5-(4-fluorobenzyloxy)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(3-methoxybenzyloxy)benzofuran-2-yl)-2H-pyran-2-one;
6-(5-(3-chlorobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
6-(5-(3-aminobenzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
6-(5-(3-(t-butoxycarbonylamino)benzyloxy)benzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
4-acetyloxy-6-(5-(3-(t-butoxycarbonylamino)benzyloxy)benzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-trifluoromethanesulfonyloxy-benzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-6-(4-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
4-acetyloxy-6-(4-acetyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-methoxybenzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
6-(5-benzyloxybenzofuran-2-yl)-3,5-dimethyl-4-hydroxy-2H-pyran-2-one;
4-acetyloxy-3,5-dimethyl-6-(5-p-toluenesulfonyloxy-benzofuran-2-yl)-2H-pyran-2-one;
4-acetyloxy-6-(7-benzyloxybenzofuran-2-yl)-3,5-dimethyl-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(5-(methoxycarbonyl)benzofuran-2-yl)-2H-pyran-2-one;
3,5-dimethyl-4-hydroxy-6-(6-methoxymethoxybenzofuran-2-yl)-2H-pyran-2-one.
The compounds represented by structural formula (I) above will sometimes form acid addition salts or base addition salts. As specific examples of acid addition salts there may be mentioned addition salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid; as specific examples of base addition salts there may be mentioned salts of metals such as lithium, sodium and potassium; salts of divalent or trivalent metals such as magnesium, calcium, zinc and aluminum; addition salts of basic amino acids such as lysine and arginine; as well as salts of ammonium and organic ammonium such as methylammonium, dimethylammonium, trimethylammonium, benzylammonium and monoethanolammonium. The present invention also encompasses hydrates of the compounds represented by structural formula (I), as well as their various solvates and crystal polymorphs.
The compounds of the invention may generally be produced by the processes outlined below in Production Processes 1 to 5, with modifications if necessary, using readily available starting substances, reagents and common synthesis methods. 
Specifically, for example, a benzofuryl-xcex1-pyrone derivative of the invention may be produced by the method shown as Production Process 1. A solution, such as a THF solution, of a 2,4-disubstituted-xcex2-keto ester is treated with 2 equivalents of a base, for example, 1 equivalent of NaH and 1 equivalent of n-BuLi, or 2 equivalents of LDA, to prepare a dienolate, and then a benzofurancarboxylic acid ester derivative is allowed to act thereon for Claisen condensation to obtain a diketo ester intermediate. The diketo ester intermediate is subjected to alkali hydrolysis and then acid treatment to obtain an xcex1-pyrone. The diketo ester intermediate can be subjected to alkali hydrolysis followed by acid treatment and then treatment with acetic anhydride and pyridine to obtain 4-acetyloxy-xcex1-pyrone, and this may be again subjected to alkali hydrolysis to yield 4-hydroxy-xcex1-pyrone. Alternatively, the diketo ester intermediate may be treated with an acid such as sulfuric acid, polyphosphoric acid or p-TsOH or heat treated under reduced pressure, to obtain 4-hydroxy-xcex1-pyrone. 
The diketo ester intermediate of Production Process 1 can also be produced by another method outlined as Production Process 2. A benzofurylketone is treated with a base such as LDA to prepare an enolate, and this is reacted with a malonic acid ester, such as malonic monomethyl ester-monochloride, to obtain a diketo ester intermediate. Alternatively, a diketo ester intermediate may be obtained by a process wherein a diketone obtained by reacting an acid chloride or ester with a benzofurylketone enolate is treated with 2 equivalents of a base such as LDA to prepare a dienolate, which is then reacted with a CO2-related compound such as carbon dioxide gas or dimethyl carbonate. 
A benzofuryl-xcex1-pyrone derivative of the invention may also be produced by the method shown as Production Process 3. A benzofuryl-xcex1-pyrone derivative can be obtained by a method in which a benzofurylketone is converted to a silylenol ether with TMSCl-Et3 or TMSOTf-Et3, for example, and this is reacted with malonic dichloride or a malonic diester. 
A benzofuryl-xcex1-pyrone derivative of the invention may also be produced by the method shown as Production Process 4. A benzofuryl-xcex1-pyrone derivative can be obtained by a method in which an xcex1-pyrone derivative with a xe2x80x94CH2X substituent at the 6-carbon (wherein X represents a leaving group such as Cl, Br, I, OMs or OTf) is reacted with a substituted salicyl aldehyde in the presence of a base such as K2CO3 and/or DBU. 
Benzofuryl-xcex1-pyrone derivatives of the invention wherein R2 (wherein R2 represents a group as defined above) is COR5 or SO2R6 (wherein R5 and R6 represent groups as defined above) can be produced by the method shown as Production Process 5. Of the benzofuryl-xcex1-pyrone derivatives according to the invention, a benzofuryl-xcex1-pyrone derivative wherein R2 is xe2x80x94COR5 may be produced by a method wherein a starting material, 6-benzofuryl-4-hydroxy-xcex1-pyrone derivative obtained by any of Production Processes 1 to 4 above, with modifications if necessary, is reacted with an acid chloride or acid anhydride in the presence of a base, for example, a tertiary amine such as Et3N or a nitrogen-containing aromatic heterocycle such as pyridine or imidazole, or alternatively, a method wherein the starting material is reacted with a carboxylic acid in the presence of a condensation agent such as WSC-HOBt, DCC-HOBt, CDI, diethyl cyanophosphate or diphenylphosphoryl azide, or by a method using the xe2x80x9cMitsunobu reactionxe2x80x9d wherein the starting material is reacted with a carboxylic acid in the presence of Ph3P-DEAD. Similarly, a benzofuryl-xcex1-pyrone derivative wherein R2 is SO2R6 may be produced by reacting a starting material, 6-benzofuryl-4-hydroxy-xcex1-pyrone derivative, with a sulfonyl chloride derivative represented by RSO2Cl, in the presence of a base, for example, a tertiary amine such as Et3N or a nitrogen-containing aromatic heterocycle such as pyridine or imidazole.
Benzofuryl-xcex1-pyrone derivatives of the present invention wherein R4 is a substituent as defined above other than hydrogen can be produced by the method shown as Production Process 6 or 7. As shown in Production Process 6, a readily available substituted salicyl aldehyde derivative is used as the starting material for any of Production Processes 1 to 5 above, with modifications if necessary, to obtain a benzofuryl-xcex1-pyrone (route A) or a 2-benzofurancarboxylic acid ester intermediate (route B) substituted with hydroxy, methoxy, formyl, bromo, nitro, etc. Route A is a method involving functional group conversion from the hydroxy, methoxy, formyl, bromo or nitro substituent at the benzofuryl-xcex1-pyrone stage, while route B is a method wherein the xcex1-pyrone ring is constructed after functional group conversion of R4 at the 2-benzofurancarboxylic acid ester intermediate stage. 
The functional group conversion of R4 from hydroxy, methoxy, formyl, bromo, nitro, etc. can be accomplished by the method shown in Production Process 7. For the benzofuran-xcex1-pyrone intermediate obtained by route A in Production Process 6, functional group conversion from hydroxyl may be accomplished by acylation with an acid chloride or acid anhydride, sulfonylation with sulfonyl chloride or sulfonic anhydride, alkylation by the Mitsunobu reaction, etc.; functional group conversion from bromo or trifluoromethanesulfonyloxy may be accomplished by carbonylation, allylation, cyanation, halogenation, amination, etc. with a transition metal catalyst such as a palladium catalyst, for example; and functional group conversion from formyl may be accomplished by alkylation or acylation with a nucleophilic agent such as an organometallic reagent or an enolate.
Functional group conversion of R4 from a 2-benzofurancarboxylic acid ester intermediate obtained by route B of Production Process 6 can also be accomplished using the same method of Production Process 7.
Production Processes 1 to 7 shown above are not intended to restrict the synthesis processes for the compounds of the invention, and any other processes known in the art may also be used.
Benzofuryl-xcex1-pyrone derivatives of the invention and their salts that are obtained in the manner described above have a triglyceride biosynthesis inhibiting effect, a blood triglyceride lowering effect and a blood HDL elevating effect, as demonstrated by Examples given below, and can therefore be used as active ingredients, in combination with the carriers, etc. described below if necessary, to provide pharmaceutical compositions, and to provide triglyceride biosynthesis inhibitors, blood triglyceride lowering agents or blood HDL elevating agents according to the invention.
For clinical application of a benzofuryl-xcex1-pyrone derivative of the invention or its salt as a prophylactic or therapeutic agent for hypertriglyceridemia, arteriosclerosis or the like, it may be administered orally or parenterally such as intrarectally, subcutaneously, intramuscularly, intravenously or percutaneously, but oral or intravenous administration is preferred.
For oral administration, it may be in the form of a solid or liquid preparation. Solid preparations include tablets, pills, powders and granules. The active substances in such solid preparations are blended with pharmacologically acceptable carriers such as sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol and carboxymethyl cellulose. The formulation may be carried out by a common method, and other additives, for example, lubricants such as calcium stearate and magnesium stearate, may also be included for formulation in addition to the carrier. Enteric coated preparations may also be prepared having an enteric coating formed by spraying the above-mentioned solid preparations with, for example, an aqueous solution or an organic solvent solution of an enteric coating substance such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate or styrene-maleic anhydride copolymer, or a methacrylic acid or methyl methacrylate copolymer. Solid preparations such as powders or granules may also be encapsulated,by enteric coated capsules.
A liquid preparation for oral administration contains, for example, an emulsifier, solution, suspension, syrup or elixir. These preparations contain conventionally used pharmacologically acceptable carriers such as water or liquid paraffin. Oily bases such as coconut oil, fractionated coconut oil, soybean oil or corn oil are also used as carriers. Pharmacologically acceptable carriers also contain, when necessary, commonly used adjuvants, aromatics, stabilizers or preservatives. A liquid preparation may be administered in the form of a capsule formed from an absorbable substance such as gelatin. Solid preparations for intrarectal administration include suppositories that are produced by known methods to contain the active ingredient.
A preparation for parenteral administration is administered as a sterile aqueous or non-aqueous solution, suspension or emulsion. A non-aqueous solution or suspension may contain propyl glycol, polyethylene glycol, a vegetable oil such as olive oil or soybean oil or an injectable organic ester such as ethyl oleate, as pharmacologically acceptable carriers. Such preparations may also contain adjuvants such as preservatives, humectants, emulsifiers, dispersers and stabilizers. These solutions, suspensions and emulsions may be sterilized by appropriate means such as, for example, filtration through a bacteria-retaining filter, heating, inclusion of a sterilizing agent or treatment with ultraviolet irradiation. After production and just prior to use of the sterile solid preparation, it may be dissolved in sterile water or a sterile injection solvent for use. Fatty emulsions prepared by adding water to a uniform solution of the active ingredients with a vegetable oil such as soybean oil and a phospholipid such as lecithin, may be homogenized with a homogenizer such as a pressure jet homogenizer or an ultrasonic homogenizer to be used as injections.
Percutaneous administration dosage forms include ointments, creams and the like. These may be produced by common methods.
When an active ingredient according to the invention is used as a treatment agent for hypertriglyceridemia or as a prophylactic agent for arteriosclerosis, it may usually be administered at about 1 to 1000 mg per day for adults, though this will depend on the patient""s condition, age, gender and body weight and the route of administration. The dosage may be administered either at one time, or over a few times, such as 2 to 6 times, per day.
The various routes of administration are preferably selected based on the absorption efficiency in the body for the particular physiologically active benzofuryl-xcex1-pyrone derivative, as determined by well-known pharmacological methods.